Pro-opiomelanocortin (POMC) is a precursor of various bioactive peptides, including adrenocorticotropic hormone (ACTH) and alpha MSH (α-MSH). α-MSH and ACTH are members of the melanocortin family, which also includes β-MSH and γ-MSH. POMC contains eight pairs of basic amino acids and one sequence of four basic amino acids, which are the sites of cleavage for the enzymes prohormone convertase 1 (PC1) and prohormone convertase 2 (PC2). Specifically, PC1 cleaves the POMC polypeptide to yield ACTH(1-39), which is in turn cleaved by PC2 to yield ACTH(1-17), which is further cleaved by PC2 to result in ACTH(1-14). A 13 amino acid α-MSH peptide is generated by the action of peptidylglycine alpha-amidating monooxygenase, which results in a C-terminally amidated α-MSH peptide. ACTH(1-17) contains the consensus amidation signal of Gly-Lys-Lys immediately carboxy the valine residue at position 13. This valine residue is subject to amidation in α-MSH and ACTH peptides. Further enzymatic modifications including N-alpha-acetylation by opiomelanotropin-acetyltransferase can occur during or after proteolytic processing. α-MSH and ACTH can be produced in amidated or non-amidated forms, as well as des-acetylated, mono-acetylated or di-acetylated forms. C-terminal amidation and/or N-terminal acetylation may contribute to the biological activity of α-MSH and/or ACTH peptides.
Under normal conditions the level of α-MSH is tightly regulated, having a half-life in the circulation on the order of a few minutes (Lipton et al. (1990) Yale J. Biol. Med. 63:173). α-MSH is found in the circulation of normal individuals at a level of about 21 pg/ml. α-MSH is also found in the aqueous humor of the eye (Taylor et al. (1992) Curr. Eye Res. 11:1199), cerebral spinal fluid (Taylor et al. (1996) Neuroimmunomod. 3:112), in skin (Luger et al. (1997) J. Invest. Dermatol. Symp. Proc. 2:87), and at sites of inflammation such as the synovial fluid of arthritic human joints (Catania et al. (1994) Neuroimmunomod. 1:321).
α-MSH and its carboxy terminal tripeptide act as in vivo and in vitro regulators of inflammation (Cannon et al. (1986) J Immunol. 137:2232; Robertson et al. (1986) Inflammation 10:371; U.S. Pat. No. 5,028,592). The mode of action of α-MSH appears to be via interference with NF-kB activation (Ichiyama et al. (1999) J Neuroimmun. 99:211). In vivo administration of α-MSH or the tripeptide α-MSH 11–13 inhibits LPS-mediated brain inflammation by preventing inactivation of I-κB and subsequent activation of NF-kB (Ichiyama et al. (1999) Brain Res. 836:31). NF-kB is a transcription factor that is necessary for the transcription of proinflammatory cytokines, including γIFN (Baeuerle et al. (1994) Ann Rev Immunol. 12:141).